HIV (Human Immunodeficiency Virus (type 1)) belonging to retrovirus is a causative virus of AIDS (Acquired Immunodeficiency Syndrome).
HIV targets CD4 positive cell groups such as helper T cell, macrophage and dendritic cell and destroys these immunocompetent cells to cause immunodeficiency.
Accordingly, a pharmaceutical agent that eradicates HIV in a living organism or suppresses its growth is effective for the prophylaxis or treatment of AIDS.
HIV possesses a bimolecular RNA gene in a shell, which is covered with an envelope protein. The RNA codes for several enzymes (protease, reverse transcriptase, integrase) characteristic of the virus and the like. Translated reverse transcriptase and integrase are present in the shell, and protease is present inside and outside the shell.
HIV contacts and invades a host cell, causes uncoating, and releases a complex of RNA and integrase and the like into the cytoplasm. From the RNA, DNA is transcribed by reverse transcriptase, and a full length double stranded DNA is produced. The DNA moves into the nucleus of the host cell and is incorporated by integrase into the DNA of the host cell. The incorporated DNA is converted to an mRNA by polymerase of the host cell, from which mRNA various proteins necessary for forming a virus are synthesized by HIV protease and the like, and a virus particle is finally formed, which then undergoes budding and its release.
These virus specific enzymes are considered to be essential for the growth of HIV. These enzymes are drawing attention as the target of the development of antiviral agents, and several anti-HIV agents have been already developed.
For example, zidovudine, didanosine, lamivudine and the like have been already on the market as reverse transcriptase inhibitors, and indinavir, nelfinavir and the like as protease inhibitors.
In addition, a multiple drug combination therapy (also often called HAART (highly active antiretroviral therapy)) concurrently using these pharmaceutical agents has been employed. For example, a combined use of three agents of “two reverse transcriptase inhibitors (zidovudine and lamivudine, or tenofovir and emtricitabine)”, and “a nonnucleoside transcriptase inhibitor (efavirenz)” or “a protease inhibitor (lopinavir, fosamprenavir or atazanavir) combined with ritonavir” have been clinically applied. Such multiple drug combination therapy is becoming a mainstream of AIDS therapy.
However, some of these pharmaceutical agents are known to cause side effects such as liver function failure, central nervous disorders (e.g., vertigo), and the like. In addition, acquisition of resistance to a pharmaceutical agent causes a problem. Even worse, emergence of an HIV that shows multiple drug resistance in a multiple drug combination therapy has been known.
Under the circumstances, a further development of a novel pharmaceutical agent, particularly a development of an anti-HIV agent based on a new mechanism, has been desired, wherein a development of an anti-HIV agent having an integrase inhibitory activity is expected, because an integrase characteristic of retrovirus is an essential enzyme for the growth of HIV.
Nevertheless, an effective integrase inhibitor has not been found as yet.
The compounds having an integrase inhibitory activity are described in the following.
WO2004/046115 (patent family: US2005/239819) describes the following compound [A] and the like, as an anti-HIV agent having an integrase inhibitory activity (see patent document 1).
wherein ring Cy is an optionally substituted C3-10 hydrocarbon group or an optionally substituted heterocyclic group; R1 is an optionally substituted C1-10 alkyl group, an optionally substituted C3-10 carbon ring group or the like; R2 is a hydrogen atom or the like; R31 is a hydrogen atom or the like; X is C—R32 or a nitrogen atom; and Y is C—R33 or a nitrogen atom (wherein R32 and R33 are independently a hydrogen atom or the like).
WO2004/046115 also describes the following compound [B] and the like, as an anti-HIV agent having an integrase inhibitory activity.

WO2005/087759 describes the following compound [C] and the like, as an anti-HIV agent having a retroviral integrase inhibitory activity (see patent document 2).
wherein R1 is H, C1-6 alkyl or substituted C1-6 alkyl; Z is —C(O)OR2 or —C(O)CH2C(O)X; X is a 5 or 6-membered aromatic or heteroaromatic ring or —C(O)OR2; R2 is H or C1-6 alkyl; R3, R4, R5 and R6 are each H, halogen, C1-6 alkyloxy, —N(R8)(R9), —C(O)CH3, —C(O)CH2C(O)X, —S(O)n—R10 wherein n is 0, 1 or 2, heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroary; R8 and R9 are each H or C1-2 alkyl; and R10 is C1-6 alkyl or the like, provided that if Z is —C(O)OR2 then at least one of R3, R4, R5 and R6 is —C(O)CH2C(O)X.
In addition, WO2005/113509 (patent family: US2006/019906) describes the following compound [D] and the like, as an anti-HIV agent having an integrase inhibitory activity (see patent document 3).
wherein ring Cy is a group selected from the group consisting of
R is a hydrogen atom or the like; R1 is
wherein R11 is —(CmH2m)—OR12, —(CmH2m)—SR12, —(CmH2m)—SO2R12 (wherein R12 is a C1-4 alkyl group and m is an integer of 1 to 4), a saturated heterocyclic group, an isopropyl group or a tert-butyl group or the like; R32 is a hydrogen atom, an ethyl group, a methoxy group or the like; R33 is a hydrogen atom or the like; and R7 is a hydrogen atom or a hydroxyl group.
However, these publications do not disclose a compound having a benzyl group substituted by a heterocyclic group at the 6-position of 4-oxoquinoline ring, or even a description suggestive thereof.
In addition, WO2006/033422 (patent family: US2006/084665) describes the following compound [E] and the like, as an anti-HIV agent having an integrase inhibitory activity (see patent document 4).
wherein ring Cy is an optionally substituted C3-10 carbon ring group or an optionally substituted heterocyclic group; R1 is a hydrogen atom, an optionally substituted C1-10 alkyl group or the like; R2 is a hydrogen atom or the like; Z is C—R31 or a nitrogen atom wherein R31 is a hydrogen atom or the like; X is C—R32 or a nitrogen atom; and Y is C—R33 or a nitrogen atom wherein R32 and R33 are each a hydrogen atom or the like.
However, this publication does not include the 4-oxoquinoline compound disclosed in this specification, or even a description suggestive thereof.    patent document 1: WO2004/046115 (page 133, Example 1-88)    patent document 2: WO2005/087759    patent document 3: WO2005/113509    patent document 4: WO2006/033422